Proteolytic processing is an essential component of normal cell growth, differentiation, remodeling, and homeostasis. The cleavage of peptide bonds within cells is necessary for the maturation of precursor proteins to their active form, the removal of signal sequences from targeted proteins, the degradation of incorrectly folded proteins, and the controlled turnover of peptides within the cell. Proteases participate in apoptosis, inflammation, and in tissue remodeling during embryonic development, wound healing, and normal growth. They are necessary components of bacterial, parasitic, and viral invasion and replication within a host.
In the normal cellular environment, proteases and their activities are regulated by tightly controlled expression, sequestration in specific cellular compartments, synthesis in an inactive precursor, or zymogen form, and by protease inhibitor molecules. Dysregulation of protease activity has recently been recognized as a significant factor in the pathogenesis of human disease. Cysteine protease activity has been correlated with the metastatic potential of tumor cells in a variety of cancers (Rochefort, H. (1992) Acta Oncol 31:125-30; Chambers, A. F. et al.(1993) Crit Rev Oncol 4:95-114; Jean, D. et al. (1996) Cancer Res 56:254-258). Altered protease activity and/or distribution plays a role in neurodegeneration, muscular dystrophy, and Huntington's disease, and in arthritis and inflammatory diseases (Ryan, R. (1995) J. Neurochem 65:1035-1045; Mantle, D. et al. (1995) J Neurological Sci 131:65-70; Huet, G. et al. (1992) Clin Chem 38:1694-1697; Lenarcic, B. et al. (1988) Biol Chem Hoppe Seyler 369 Suppl:257-261).
The protease inhibitors play a major role in the regulation of the activity and effect of proteases. They have been shown to control pathogenesis in animal models of proteolytic disorders (Murphy, G. (1991) Agents Actions Suppl 35:69-76). In particular, low levels of the cystatins, low molecular weight inhibitors of the cysteine proteases, seem to be correlated with malignant progression of tumors (Calkins, C. C. et al (1995) Biol Chem Hoppe Seyler 376:71-80). The balance between levels of cysteine proteases and their inhibitors is also significant in development of disorders. Specifically, increases in cysteine proteases levels, when accompanied by reductions in inhibitor activity, are correlated with increased malignant properties of tumor cells and the pathology of arthritis and immunological diseases in humans. The first human cystatin was isolated from sera of patients with autoimmune disease and has been found in all human tissues examined (Chambers, A. F et al. (1992) Mol Carcinog 5:238-245; Rozhin, J. et al. (1990) Cancer Res 50:6278-6284; Brzin, J. et al (1984) Biochem Biophys Res Commun 118:103-109; Abrahamson, M. et al (1990) Biochem J 268:287-294).
Protease inhibitors have proved to be effective therapeutics for the diminution of the viral load in HIV infection, and have been shown to arrest Trypanosom a cruzi replication in mammalian cells and to suppress the in vivo replication of rotavirus and coronaviruses. Additionally, protease inhibitors are able to inhibit growth of all strains of group A streptococci, including antibiotic-resistant strains (Shapiro, J. M. et al (1996) Ann Intern Med 124:1039-1050; Stoka, V. (1995) FEBS. Lett 370:101-104; Vonderfecht, S. et al (1988) J Clin Invest 82:2011-2016; Collins, A. et al (1991) Antimicrob Agents Chemother 35:2444-2446)
The discovery of molecules related to human cystatin-like protein and the polynucleotides encoding them, satisfies a need in the art by providing new diagnostic or therapeutic compositions useful in diagnosing and treating cancer, immunological conditions, neurodegenerative conditions, muscular dystrophy, Huntington's disease, viral, bacterial, and parasitic diseases.